Evaluating the impact of school-based influenza vaccination programme on absenteeism and outbreaks at schools in Hong Kong: a retrospective cohort study protocol

Introduction Seasonal influenza causes annual school breaks and student absenteeism in Hong Kong schools and kindergartens. This proposal aims to conduct a retrospective cohort study to evaluate the impact of a school-based influenza vaccination (SIV) programme on absenteeism and outbreaks at schools in Hong Kong. Methods The study will compare schools that implemented the SIV programme with schools that did not. The data will be sourced from school records, encompassing absenteeism records, outbreak reports, and vaccination rates. We will recruit 1000 students from 381 schools and kindergartens in 18 districts of Hong Kong starting June 2024. The primary outcome measures will include absenteeism rates due to influenza and school influenza outbreaks. Secondary outcomes will consist of vaccination coverage rates and the impact of the SIV programme on hospitalisations due to influenza-like illness. A t-test will be conducted to compare the outcomes between schools with and without the SIV programme. Ethics and dissemination The school completed signing the participants’ informed consent form before reporting the data to us. Our study has been approved by the Hospital Authority Hong Kong West Cluster IRB Committee (IRB No: UW 17–111) and was a subtopic of the research “The estimated age-group specific influenza vaccine coverage rates in Hong Kong and the impact of the school outreach vaccination program”. Trial registration This study will be retrospectively registered. Supplementary Information The online version contains supplementary material available at 10.1186/s41043-024-00561-z.


Introduction
Influenza is a contagious respiratory tract infection caused by the influenza virus in humans [1,2].In Hong Kong, seasonal influenza occurs more often from January to March/April and from July to August (online supplemental material 1).As of February 9, 2024, the flu hospitalisation rate for the 0-5-year-old group in Hong Kong is 1.432 per 10,000 people, and the flu hospitalisation rate for the 6-11-year-old group is 0.896 per 10,000 people.Among them, the 0-5-year-old group has the highest flu hospitalisation rate among all age groups in Hong Kong (online supplemental material 2).The paediatric population is generally at the most significant risk of influenza virus infection among all age groups, and influenza-related hospitalisation rates are high in schoolage children [3].The influenza vaccine is one of the most effective ways to prevent influenza.It is recommended by the Centre of Health Protection (CHP) that all people aged six months or above should receive the influenza vaccine for personal protection [3].
In the 2018/2019 winter season, the CHP reported 864 influenza-like-illness (ILI) institutional outbreaks, with 61% and 21% of outbreaks occurring in kindergartens (KG)/children care centres (CCC) and primary schools, respectively (online supplemental material 3).The influenza-associated hospital admission rate of children under 5 was the weekly peak, followed by elderly 65-year-old and 6-11-year-old children, demonstrating that young children are vulnerable to infection by seasonal influenza.
To increase the vaccination rates among primary school children, starting from the 2018/19 season, the Hong Kong Department of Health (DH) launched the School Outreach Vaccination Pilot Programme.All primary schools, including KGs, KG-cum-CCCs, CCCs and special CCCs, are eligible to apply and join the programme.81.5% of primary schools and 72.7% of kindergartens have signed up for the free Seasonal Influenza Vaccination School Outreach Programme [4].According to CHP data, the vaccination rate among children between 6 and 12 years has significantly increased by 205.1%, compared to the vaccination rate in 2017/18 [3].
The SIV programme is beneficial for preventing school absenteeism [5].During the 2009 H1N1 pandemic, the Hong Kong government closed all KGs and primary schools for a prolonged period (online supplemental material 4), resulting in high rates of school absenteeism [6].This plan interrupted student learning, and absenteeism negatively impacted teaching work productivity and pace [7,8].Although there is no guideline for territorywide school closure in Hong Kong, future influenza outbreaks at the school level are likely to result in higher rates of absenteeism, and individual school closures will likely be in large-scale outbreaks or those with severe health outcomes (online supplemental material 5).
There is limited literature investigating the impacts of a school-based influenza vaccination (SIV) programme on school absenteeism and outbreaks in Hong Kong.Additionally, this aspect of influenza vaccination in school children is paramount in limiting the negative impacts, like absenteeism during an influenza outbreak.It is critical to optimise the Seasonal Influenza Vaccination School Outreach Programmes.
In this sense, a retrospective cohort study is designed to examine the potential effects of SIV programs on participating primary schools and kindergartens in Hong Kong to address the gaps and provide valuable insights.
Several countries, including the US, Italy, Russia, and Japan, have conducted school-based immunisation programmes in primary schools [4].Studies evaluating the impacts of school-based influenza in the US and Japan have concluded that increased influenza vaccination rates effectively reduce school absentee rates [9,10].However, some studies have shown that school-based influenza moderately impacted absenteeism [11,12].In Hong Kong, the existing school outreach programme successfully reduced the ILI rate and hospitalisations in primary school students from 2018 to 2019 [4].Nevertheless, there are still limited studies examining the potential impact of the SIV programme on school outbreaks and absenteeism (online supplemental material 6) [4].
The expected outcomes of this retrospective observational study are as follows: Among 0-5-year-old children participating in the school flu vaccination program, flu-related hospitalisations are approximately 1.432 per 10,000 individuals; among 6-11-year-old children, the corresponding frequency is approximately 0.896 per 10,000.In each school participating in the flu vaccination program, the vaccination rate of students is at least 40%.Many students choose to be vaccinated with liveattenuated vaccines over inactivated ones.In schools participating in the flu vaccination program, the student attendance rate has increased by at least 1% compared to before.Students can wear masks consciously during flu-prone seasons and pay attention to hand hygiene.The parents of students participating in the school flu vaccination program can reduce the number of student absences and hospitalisations, thereby alleviating the health and financial burden on the family.

Literature review
Typically, hospitals would recommend seasonal flu vaccines.However, the high cost of vaccination is a significant concern.A double-blind, randomised, controlled study shows that children's respiratory tract infections can directly impose a significant financial burden on the family, indicating that the medical expenses for respiratory tract infections in children are high.At the same time, the safety and effectiveness of vaccines are relatively low, which makes parents reluctant to vaccinate their children [13].In the past, attempts to send text messages to pregnant women in middle-and high-income areas failed to increase their vaccination enthusiasm [14].Analysing the factors that prevent parents from having their children vaccinated from the perspective of the vaccine type, although vaccinating children with the live attenuated influenza vaccine (LAIV) is more effective in reducing the incidence of flu per 1,000 person-days than the inactivated influenza vaccine (IIV) [15], parents generally prefer not to choose the live attenuated influenza vaccine (LAIV) for their children.
On the one hand, inactivated influenza vaccines are relatively cheaper than live attenuated influenza vaccines; on the other hand, parents need to manage their children's vaccines carefully and receive regular booster vaccinations [16].However, since 2016, how flu vaccines attract parents has gradually shifted from the cost of vaccination to vaccine education.A controlled trial for junior and senior high school students found that once parents receive good flu vaccine education, their willingness to vaccinate their children will be positively motivated, regardless of whether the flu vaccine requires additional expenses [17].The results of a meta-analysis suggest that the main reason for voluntary and active flu vaccination is the vaccine's effectiveness rather than forced or threatening behaviours [18].A report suggests that different vaccine communication channels can be used for vaccinated people of different ages, effectively reducing the vaccine cost to balance vaccine costs [19] research and development, vaccination, and publicity [19].This result means the top priority should be to develop more effective and safer vaccines to increase the flu vaccination rate of the 0-11-year-old group, which is only the case in some countries worldwide [20].
Another strategy is derived from the application of flu vaccines in adults.One of the targets was to find whether adults would directly benefit from getting flu vaccines at work or in life, thereby indirectly promoting the popularity of flu vaccine vaccinations.Vaccination can significantly reduce the incidence of flu-related diseases and the number of work absences [21], which means that vaccination has become a strategy for people to avoid getting sick and being absent from work.If not vaccinated, children should wear masks actively to prevent the spread of the disease through the air [22].To further increase the coverage of flu vaccine vaccinations among teenagers, public health intervention measures have gradually attracted public attention.Public health commissioners enter the campus, distribute vaccine education booklets to students, and collaborate with campus leaders to carry out vaccine awareness-raising activities to increase the willingness and enthusiasm of students and parents to get flu vaccines.After the "campus vaccination program" matures gradually, public health commissioners also use communities as a unit and work with community hospitals and family doctors to continuously convey the concept of flu vaccine prevention to the public, thereby further increasing the flu vaccine coverage of teenagers [23].Another target was to determine measures in the information-scarce and relatively underdeveloped suburban and rural areas to increase flu vaccine coverage in remote areas such as suburbs and rural areas.Unlike in the past, when public health commissioners educated students on campus, inviting parents to enter the campus in rural areas to receive vaccine education can increase parents' willingness to consent to vaccination [24].Vaccination has gradually been extended to schoolaged children to develop primary health care, and there are different degrees of resistance during the promotion period.Implementing the school flu vaccination program is significantly correlated with the increase in the vaccination rate of students in suburban schools [25].A third target was to find whether promoting school flu vaccination could drive the popularisation of student vaccinations.Surveys in American urban schools suggest that telephone and text message interventions cannot significantly increase the vaccination rate of flu vaccines [26].When the UK promotes the national childhood flu vaccination program, it is believed that providing parents with behavioural-informed letters and email or text message reminders can increase the popularity of school vaccines [27].
The geometric titer (GMT) of the attenuated recombinant live influenza vaccine (Alice strain) reached 189.6, which initially endows this vaccine with antigenicity and safety [28].It was not until 1985 that the trivalent inactivated influenza B vaccine could provide a 64% antiinfection protection rate for school-aged children aged 6-19 [29].After school-aged children are vaccinated with seasonal influenza vaccines, the vaccine efficacy against diagnosed influenza A (H3N2) and influenza B infections is 31% (95% confidence interval: -138%, 80%) and 96% (95% confidence interval: 67%, 99%) respectively [30].In a double-blind, randomised, controlled clinical trial in eastern China, the effectiveness and safety of the liveattenuated influenza vaccine for minors (3-17 years old) were verified, and the effectiveness of the vaccine against all types of influenza reached 62.5% (95% CI: 27.6-80.6)[31], which provides a theoretical basis for preventing influenza infections in Hong Kong children aged 0-11.With the early advocacy of the campus influenza vaccine program by the public health departments of many countries worldwide, in-depth research was required on topics including whether this program could be a blessing for children on campus, whether it could effectively improve the immunity of students against the flu, and whether it could guarantee the health and education of students and avoid absence due to flu hospitalisation.After researchers piloted the flu immunisation program in schools, it was found that student attendance increased significantly by 0.8-1.9%compared to before [32].It is unknown whether all the reasons for student absences are from the flu.With the gradual enrichment of vaccine types, clinical observations have found that applying live-attenuated vaccines to the entire age group of elementary school students provides more significant influenza immune protection than inactivated vaccines [33].In the past, it was generally believed that a single vaccination of influenza vaccine for children aged 4-6 could obtain influenza immunity.
Combined vaccination was then found to achieve better cross-immune protection [34].
Once students can benefit from the flu vaccine, it can not only fundamentally promote the popularity of the flu vaccine but also, to a certain extent, guarantee children's education.The United States has established a national strategic goal: the coverage rate of children's flu vaccines in the entire United States should not be less than 80%.Compared with traditional vaccination in community hospitals, implementing the campus flu vaccination program achieves America's strategic goal [35][36][37].
A study in New York believes that building a reasonable cost-benefit system for flu vaccines can increase the coverage of flu vaccines for school-aged children, increasing the flu vaccine coverage of first-and second-grade students in elementary schools by 11.2 and 12.0% points [38].According to a cross-sectional observation report, 42,487,816 student days of absence were accumulated in Northern California from 2011 to 2018.However, the city-wide school flu vaccination can reduce the student flu absence rate [39].In general, student vaccination against the flu can reduce the number of times they get sick and are hospitalised and prevent large flu outbreaks, thereby reducing the number of absences from class [40].Further studies were required for questions, including whether vaccinations of students were against the flu and whether the reduction in the number of absences from class was an independent influencing factor.

Study objectives
The main objective is to understand the impacts of the SIV programmes at the primary schools and kindergarten level, including absenteeism and outbreaks.This object is indicated by the steps involving recruitment of schools into different groups (SIV and non-SIV), data collection through self-reporting from the schools, and subsequent data analysis.
The research question was whether an SIV programme would be associated with reduced absenteeism and outbreaks for kindergartens and primary schools compared with schools that do not join the programme.We plan to recruit 1000 primary school and kindergarten students in Hong Kong.

Study design, setting and recruitment
The study will be conducted in Hong Kong primary schools and kindergartens, and it will include records of student absenteeism and reported outbreaks.Schools that participated in the influenza vaccination program and those that did not will be included to assess the program's direct impact compared to the general population.The selection of schools will be based on the availability of complete data for the specified periods.School administrators will be contacted, and informed consent will be obtained for using their records in the study.The study is divided into two periods for comparison: the pre-intervention period (2016/17 and 2017/18 academic years) and the post-intervention period (2018/19 and 2019/20 academic years, Fig. 1).This design allows for examining trends and differences in absenteeism and outbreak rates before and after the implementation of the vaccination program.
Kindergartens and primary schools registered under the Education Bureau in Hong Kong will be selected by stratified random sampling in each of the 18 districts.The list of local kindergartens and primary schools that had joined and not joined the SIV Programs in 18 districts in two different periods was constructed.
Defining Strata: the strata are the 18 districts of Hong Kong.Each district serves as a separate stratum.
Random Sampling within Each Stratum: use a random sampling technique within each district (stratum) to select schools.This step can be done using a random number generator or a similar method to ensure that every school on the list has an equal chance of being selected.
Documentation and Reproducibility: Document the sampling process in detail to ensure the study's reproducibility.This step includes recording the method used for random selection and any criteria for including or excluding certain schools.
Ethical Considerations: ensure that the selection process is fair and unbiased.Maintain confidentiality and adhere to ethical standards in research.
Selected schools will be invited to join the research by sending invitation letters and emails.Follow-up phone calls to the principals or their delegates of the schools will be made to ensure their receipt of the invitations, clarify details of the study, and recruit their schools further to participate in the study.The anonymous information on influenza vaccination records and data will be collected from the institutions included.

Outcome measures Primary outcomes measures
Absenteeism rates: Compare the difference in absenteeism rates due to influenza and school influenza outbreaks among students in schools with and without SIV programs.Schools participating in the study were required to provide sufficient supporting materials to provide detailed data reports on student absenteeism.However, schools were required to trace student absenteeism before participating in the SIV program to pass the data verification successfully.

Secondary outcomes measures
Hospitalisation rates: Compare the hospitalisation rates due to influenza and school influenza outbreaks among students in schools with and without SIV programs.Schools participating in this study must provide sufficient supporting materials to illustrate detailed data reported on student hospitalisations.
Vaccination rates: Compare the differences in vaccination rates among students in schools with SIV programs and schools without SIV programs.

Data collection
Retrospective data covering four academic years will be collected from schools that joined the SIV Programme (SIV group) and those that did not participate (non-SIV group).Data from 2016/17 to 2017/18 will be designated as "pre-SIV years" because the SIV Programme was not yet launched, while data from 2018/19 to 2019/20 will be designated as "SIV years".
Three data sets from schools that agreed to join the study will be self-reported.First, data on half-day absences in each grade every month will be aggregated.As reasons for student absences can vary and may not be recorded by schools, all excused and unexcused absences will be counted.Second, the number of outbreaks per school year will be collected each month.As schools must report to CHP for respiratory tract infection outbreaks (i.e., three or more students in the same class developed symptoms), the school has such data on record.Third, basic information about the schools will be reported, including the number of students in each grade, the total number of school days per year and the year of joining the SIV programme, districts of school location, number of school days, grade of students, and healthcare access.

Sample size calculation
We hypothesize that the school-based influenza vaccination will result in a decrease in the rate of absenteeism from a baseline rate (prior to the intervention).
Assuming the baseline absenteeism rate is 5% (preintervention period) and anticipating a reduction to 3% post-intervention period, we will calculate the sample size required to detect this difference with sufficient statistical power.
The sample size for each group (schools with and without the vaccination program) can be calculated using the formula for comparing two proportions in cohort studies.This calculation will account for the expected absenteeism rates, the desired power of the study (typically 80% or 0.80), and the significance level (typically 5% or 0.05).
Using the standard formula: Where: • p 1 = 0.05 (baseline absenteeism rate without the intervention).• p 2 = 0.03 (expected absenteeism rate with the intervention).• Z α/2 is the Z-score corresponding to the 95% confidence level (typically 1.96).• Z β is the Z-score corresponding to the power of 80% (typically 0.84).
After calculating, we determine the required sample size for each group.Suppose the calculation results in a sample size of 1,000 students per group; considering the design effect due to clustering within schools (e.g., design effect = 1.5 due to the intra-class correlation within schools), the adjusted sample size would be 1500 students per group.
Since schools vary in size, the number of schools needed to reach this sample size depends on the average number of students per school.For example, if the average school size is 300 students, five schools would be needed for each group of 10 schools.
However, the study aims to include a broader representation.Therefore, considering potential dropouts and missing data, we might aim to recruit more schools.If we estimate a 10% dropout or missing data rate, the target recruitment would be increased accordingly.
Therefore, for primary schools, if 272 schools participated and the remaining 109 did not (with a similar approach for kindergartens), we ensure the study has enough power to detect the anticipated differences in absenteeism rates while accounting for variations in school size and potential data loss.

Descriptive analysis
Initially, a descriptive statistical analysis will be conducted to summarize the characteristics of the study population, including school demographics, student demographics (e.g., age, gender distribution), baseline absenteeism rates, and influenza vaccination coverage rates for both the pre-and post-intervention periods.This analysis will utilize means and standard deviations for continuous variables and frequencies and percentages for categorical variables.

Difference-in-differences (DiD) analysis
The core of the analysis will be a Difference-in-Differences (DiD) approach, comparing changes in absenteeism and outbreak rates from the pre-to the post-intervention period between schools that participated in the vaccination program and those that did not.This method helps to control for time-invariant unobserved heterogeneity between the treated and control groups and isolates the effect of the intervention by considering the differential effect over time.
The DiD estimator will be calculated using the formula: where Y represents the outcome variable (absenteeism rate or outbreak rate).

Multivariable logistic regression models
Multivariable logistic regression models will be utilized to adjust for potential confounders and better understand the relationship between the influenza vaccination program and the outcomes (absenteeism and outbreaks).These models will include the intervention variable (vaccination program participation), time (pre-or postintervention), and an interaction term between the intervention and period to estimate the DiD coefficient.Control variables will include school size, demographic characteristics, and other health interventions that might influence the outcomes.

Subgroup analyses
Subgroup analyses will be conducted to explore the differential effects of the influenza vaccination program across various demographic and school characteristics (e.g., primary vs. secondary schools, gender, and age groups).The regression models will include interaction terms between the intervention and these subgroup identifiers to test for significance.

Sensitivity analyses
Sensitivity analyses will be performed to assess the robustness of the study findings, which could include alternative specifications of the regression models, using different definitions of absenteeism and outbreaks and excluding schools with extreme values or missing data.These analyses help to identify whether the main findings are consistent across different assumptions and methodologies.

Power and sample size considerations in analysis
The statistical analysis plan incorporates the sample size calculations previously detailed, ensuring that the study is adequately powered to detect the hypothesised differences in outcomes.The analysis will account for data clustering within schools through cluster-adjusted standard errors or multilevel modelling techniques, as appropriate, to provide accurate confidence intervals and p values.

Handling missing data
The approach to handling missing data will be detailed, considering using multiple imputation techniques if the missingness is assumed at random (MAR) or conducting sensitivity analyses under different missing data assumptions if not MAR.

Additional details
According to the needs assessment in the introduction, most institutional outbreaks of ILI have been recorded in primary schools and kindergartens, and local evidence is necessary to understand whether it is appropriate to allocate more resources to implementing and promoting school-based vaccination programmes.Therefore, a retrospective cohort study evaluating the impact of SIV programmes on absenteeism and outbreaks at schools is proposed.
To further prevent and control the incidence and outbreaks of influenza among young children, researchers must conclude whether school-based vaccination programmes can offer indirect benefits in addition to reducing the ILI rate and hospitalisations.By providing local solid evidence, the government can understand whether allocating more resources to implement and promote school-based vaccination programmes is appropriate.With information from authorities, more schools can be encouraged to join the programme, and parents can be advised if more indirect benefits can be confirmed.
Our team believes this retrospective study could be a reference point for future similar studies and a preliminary guide for the Food and Health Bureau to optimise the school-based vaccination programme soon.We sincerely hope that our proposal will be taken into serious consideration.

Control of Bias and Confounders
Monitoring and evaluating the impact of the SIV programme is challenging due to the reliance on selfreported data from schools, which can be subject to biases or inaccuracies.The COVID-19 pandemic has affected Hong Kong since early 2020, and school closures have affected school days.The collected data would be inaccurate, incomprehensive, and unrepresentative if we conducted a prospective cohort study.Even if the face-toface teaching mode is resumed, wearing masks and stringent hand hygiene practices at schools would also affect the transmission of infectious diseases, thus affecting the results.Therefore, our team chose to adopt a retrospective cohort-based approach instead of a prospective one to minimise the effects of the COVID-19 pandemic on the study results.
To control confounding variables that may affect absenteeism and the number of outbreaks at school, we use multiple linear regression models to adjust known confounders, including districts of school location, number of school days, and number of students in each grade.In addition to the confounders we have identified, here are more potential confounders that we might consider when analysing absenteeism and outbreak rates in schools, such as preexisting health conditions of students and school transportation mode since they might play a role in exposure to infectious agents.Subgroup analyses will also evaluate the program's impact on different age groups and socioeconomic backgrounds.

Limitations
Potential limitations of the study include the retrospective design, reliance on school-reported data, and the potential for unmeasured confounding factors.Efforts will be made to mitigate these limitations through rigorous data validation processes and statistical adjustments for known confounders.
The observational nature of this study may not establish a definitive causal relationship between the SIV Programme on school-based influenza outbreaks and absenteeism.However, an observed relationship between school vaccination and the study parameters may still indicate an underlying impact, whether by direct effects of the SIV Programme or indirect effects of vaccination initiatives.The direct ones would be the reduced incidence of influenza among vaccinated students, causing fewer absenteeism and outbreaks directly attributable to the vaccination.Indirect ones occur when the vaccination of a portion of the population protects unvaccinated individuals.This situation happens as the disease's overall prevalence decreases, reducing the likelihood of the disease spreading to those not vaccinated.
Odds and risk ratios may indicate the degree of associated difference in the odds and risks for outbreaks and absenteeism for schools that joined the SIV programme.
First, this observational study could not investigate whether the relationship between the SIV programme, absenteeism and school outbreaks is causal.This study would also suffer from other confounding factors that have not been controlled in the analysis, such as reasons for the absence and types of influenza vaccine administered.Research examining the causal relationship between them could be conducted in the future.Second, the study was conducted retrospectively, and data were collected by self-reporting from schools, which may lead to incomprehensive data and recall bias.Third, some students in non-SIV schools may have already been vaccinated outside school settings because they were parentled, which could affect the result of the analysis.Finally, schools are recruited to join the study voluntarily.The study's sample size is primarily influenced by the willingness of schools to participate, and a small sample size would affect the study's external validity and statistical significance (Table 1).

Significance
Evidence gathered from this proposed study will provide valuable insights into the effectiveness of SIV programmes in reducing absenteeism and preventing school outbreaks.This study aims to have a fair representation of all kindergartens and primary schools in Hong Kong; as such, stratified random sampling within the 18 districts of Hong Kong will be adopted.Therefore, all the results will inform Hong Kong's public health influenza prevention and control strategies.Furthermore, this proposed study is expected to contribute to the existing knowledge on the impact of SIV programs and provide evidence to support the implementation and expansion of such programs in Hong Kong and other similar places.

Conclusion
Despite challenges such as logistical hurdles, parental consent issues, and uneven vaccine uptake, preliminary data suggests a positive impact on reducing influenza-like illness rates and student hospitalisations.Future studies should focus on improving vaccine coverage and addressing barriers to access, particularly in underserved areas, to maximize the programme's effectiveness.Continued evaluation and adaptation of the programme based on local needs and outcomes will be crucial for its success in enhancing public health among school-aged children.